Dr. John T. Farrar, Assistant Professor of Neurology at the University of Pennsylvania Medical Center (UPMC) is applying for a Clinical Investigator Award to pursue an academic career focusing on the clinical investigation of cancer pain evaluation and management. Cancer is a growing cause of death and disability responsible for 1 out of every 5 deaths in the United States. Fear of pain and suffering are a major concern to most patients who develop cancer. Despite advances in pain management, less than half receive optimum and effective therapy. Beyond the proven effectiveness of opiates, there are very few well designed studies on which to base a judgment of how to best treat these patients. Tricyclic antidepressants are used in up to 40% of cancer patients. While they have been shown to significantly reduce noncancer neuropathic pain and reduce the amount of opiates used in the postoperative setting, they have not been well studied in cancer patients. Establishing their true efficacy and determining factors which predict the groups that may benefit would substantially influence cancer patient care. Dr. Farrar has a long-standing interest in clinical pain management in oncology patients, has established a Clinical Cancer Pain Management Group, and is pursuing the UPMC Master of Science Degree Program in Clinical Epidemiology. His interests include prognostic modeling and pharmacoepidemiology as applied to the understanding of cancer pain evaluation and management. The application requests support to allow him to undertake a comprehensive career development program including: formal course work leading to a M.S. in Clinical Epidemiology: a research preceptorship with Dr. Brian Strom, Director of the Center for Clinical Epidemiology and Biostatistics; extensive consultation with Dr. Russell Portenoy, Associate Professor of Neurology and Director of the Analgesic Pain Service at Memorial Sloan Kettering Cancer Center; and a research project, that will help provide the knowledge and skills necessary to pursue a successful career as an independent investigator. The proposed study is a double-blind randomized placebo-controlled trial to determine the efficacy of adjuvant therapy with amitriptyline (balanced nonadrenergic and serotonergic) and desipramine (primarily noradrenergic) against the active placebo benztropine (to produce a similar side effect spectrum), in cancer patients with pain that is not optimally controlled by opioid therapy. Therapy will be titrated from 12.5 to 150 mg in 10 weeks to maximum dose or unacceptable side effects. To determine a possible prediction model for the likely responders, the data will be re-analyzed as a cohort study. Blood samples will be drawn to evaluate if analgesia is related to anti-depressant blood levels. The results of this study will substantially impact on the care of cancer pain by either proving or disproving the efficacy of these commonly used drugs, and by providing specific guidance for which group of patients where they stand to benefit from this therapy.